Microbiota-responsive oral nano-amifostine enables colorectal-specific radioprotection and tumor immunity via gut microenvironment reprogramming.

Radiotherapy for abdominal malignancies is limited by intestinal toxicity and secondary colorectal cancers. Here, we develop an oral, microbiota-responsive nano-amifostine (CS/PEC-AMF NPs) system that achieves site-specific radioprotection in the colorectum without compromising antitumor efficacy. By conjugating amifostine to pectin and encapsulating it with chitosan, the nanoparticles enable pH- and microbiota-triggered release in the large bowel, safeguarding drug bioactivity during gastrointestinal transit. In murine models, CS/PEC-AMF NPs attenuate both acute and chronic radiation-induced bowel injury, restore epithelial integrity, preserve stem cell populations, and promote tight junction repair. Integrated metagenomic and metabolomic analyses reveal that the system normalizes gut microbiota diversity and composition, increases short-chain fatty acid production, and facilitates macrophage polarization towards the anti-inflammatory M2 phenotype. Notably, the formulation synergistically enhances tumor suppression and extends survival in orthotopic colorectal tumor models undergoing radiotherapy and reduces the incidence of secondary colorectal tumors post-irradiation. Mechanistically, transcriptomic analysis demonstrates the suppression of proinflammatory pathways and the promotion of DNA repair programs. This study provides a paradigm for leveraging functional nanomaterials to orchestrate precise, tissue-specific radioprotection and immune modulation, addressing a key challenge in abdominal cancer therapy. Supplementary Information: The online version contains supplementary material available at 10.1007/s42114-025-01492-x.